The invention relates to stable pharmaceutical solution to be used with pressurised metered dose inhalers (MDIs) suitable for aerosol administration. In particular, the invention relates to solution to be used with pressurised metered dose inhalers (MDIs), suitable for aerosol administration containing xcex22-agonists and stable at room temperature for a pharmaceutically acceptable shelf-life.
Pressurised metered dose inhalers are well known devices for administering pharmaceutical products to the respiratory tract by inhalation.
Drugs commonly delivered by inhalation include bronchodilators such as xcex22-agonists and anticholinergics, corticosteroids, anti-leukotrienes, anti-allergics and other materials that may be efficiently administered by inhalation, thus increasing the therapeutic index and reducing side effects of the active material.
MDI uses a propellant to expel droplets containing the pharmaceutical product to the respiratory tract as an aerosol. Formulations for aerosol administration via MDIs can be solutions or suspensions. Solution formulations offer the advantage of being homogeneous with the active ingredient and excipients completely dissolved in the propellant vehicle or its mixture with suitable co-solvents such as ethanol. Solution formulations also obviate physical stability problems associated with suspension formulations so assuring more consistent uniform dosage administration.
For many years the preferred propellants used in aerosols for pharmaceutical use have been a group of chlorofluorocarbons which are commonly called Freons or CFCs, such as CCl3F (Freon 11 or CFC-11), CCl2F2 (Freon 12 or CFC-12), and CClF2xe2x80x94CClF2 (Freon 114 or CFC-114).
Recently, the chlorofluorocarbon (CFC) propellants such as Freon 11 and Freon 12 have been implicated in the destruction of the ozone layer and their production is being phased out.
Hydrofluoroalkanes [(HFAs) known also as hydro-fluoro-carbons (HFCs)] contain no chlorine and are considered less destructive to ozone and these are proposed as substitutes for CFCs.
HFAs and in particular 1,1,1,2-tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA 227) have been acknowledged to be the best candidates for non-CFC propellants and a number of medicinal aerosol formulations using such HFA propellant systems have been disclosed.
Due to the higher polarity of the HFA propellants, in particular of HF A 134a (dielectric constant Dxe2x89xa79.5), with respect to CFC vehicles (Dxe2x89xa62.3), HFA solution formulations may suffer to a greater extent of chemical stability problems with respect to the corresponding CFC formulations.
Preparation of stable HFA solution formulations is even more critical when bronchodilator xcex22-agonists belonging to the class of the phenylalkylamino derivatives are concerned; said drugs, like formoterol, 8-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl] amino] ethyl]-2(1H)-quinolinone (hereinafter referred as TA 2005), and salbutamol (albuterol) and others, may suffer of inherent chemical stability problems due to their susceptibility to oxidative conditions; moreover, in the view of the presence of some functional groups like formamide, a higher polarity of the vehicle may accelerate the rate of solvolysis reactions.
As far as formoterol, the currently marketed CFC solutionformulation (Foradil(copyright)) exhibits a limited shelf life, i.e. 12 months at refrigerator temperature, 4xc2x12xc2x0 C., and only 3 month at room temperature.
As far as salbutamol, no formulation as HFA solution for aerosol administration currently on the market.
In the case of TA 2005, no formulation at all is currently available for aerosol administration.
In consideration of the problems outlined, it would be highly advantageous to provide a formulation in the form of HFA solution to be administered by MDI""s aimed at providing pharmaceutical doses of xcex22-agonists characterised by adequate shelf-life.